FDA action clears way for cancer imaging agent research

February 2, 2009

FDA approval of a multicenter investigational new drug application has cleared away regulatory obstacles that stood in the way of definitive trials to establish the clinical efficacy of a PET imaging agent that measures cell proliferation in cancerous tumors.

FDA approval of a multicenter investigational new drug application has cleared away regulatory obstacles that stood in the way of definitive trials to establish the clinical efficacy of a PET imaging agent that measures cell proliferation in cancerous tumors.

Molecular imaging researchers have touted F-18-labeled 3'-deoxy-3'-fluorothymidine (FLT) for the potential complementary role it could play with FDG for cancer imaging. F-18 FLT-PET generates a quantifiable measure of cell proliferation, a potential biomarker for tumor aggressiveness and the response of cancers to therapy. FDG measures cellular glucose metabolism, a marker for the presence of metastatic disease and therapeutic response.

Mixed results have been reported for FLT in single-center clinical trials. It has shown considerable promise as a biomarker of response to investigational drugs but has produced inconsistent results for cancer detection, staging, and restaging. Commercial diagnostic pharmaceutical companies have not pursued a standard FDA new drug application for F-18 FLT because of its status as a generic radiopharmaceutical agent that is not available for patent protection or exclusive manufacturing rights.

The SNM sponsored and strongly supported the centralized multicenter investigational new drug (IND) application.

The approval of multicenter chemistry manufacturing and controls in the FLT IND represents the successful demonstration of an important FDA IND review process for PET imaging biomarkers, according to the SNM. The FDA agreed to allow multiple generators of the FLT agent to be evaluated, reviewed, and accepted for use under a single IND application, thereby eliminating the expense and time needed for each facility to pursue an IND individually. The agency also agreed to base the IND review process for acceptance of the various investigational FLT products on the end product specifications.

The SNM combined National Cancer Institute information with information obtained from the University of Pennsylvania, Mayo Clinic, University of Iowa, University of Utah, and University of Washington.

Most of these institutions hold a single-site approved IND for FLT, but each facility follows a different manufacturing process, according to the SNM. The individual INDs describe end product FLT that is unique to each facility. Prior to the new centralized IND submission, the FDA has not been asked to review these various production processes together or to base acceptance of the chemistry manufacturing and controls on the end product formulation.

"If you are a pharmaceutical company trying to do a clinical trial across a number of different facilities, having the ability to do imaging only at a single site was a limitation," said SNM president Robert W. Atcher, Ph.D, in an interview.

Centralized multicenter INDs are a key enabler for the recently formed SNM Molecular Imaging Trials Network, whose mission is to increase the use of imaging biomarkers in multicenter clinical trials.

The decision comes as good news for pharmaceutical companies that want to use F-18 FLT-PET as a surrogate marker to measure the effectiveness of experimental drug therapies in humans. Access to the agent may speed and simplify drug development, Atcher said.

"Until now, FLT has been evaluated for investigational use under an IND at a limited number of imaging centers that have FDA-approved INDs in place," he said in a release. "With the SNM's centralized IND now approved, multicenter investigational imaging is achievable in large (100+ center) therapeutic clinical trials through a single cross reference letter."

Support from the National Cancer Institute was crucial to securing the multicenter IND, according to the SNM. The society noted that the NCI has allowed more than 20 entities to cross-reference this master IND since 2005.

"The NCI had pharmacology and toxicology data that were critical for our application," Atcher said. "Without the NCI, it would have been difficult to move forward."

For more information from the Diagnostic Imaging and Search Medica archives:

New SNM research network lays groundwork for molecular imaging clinical trialsReport from SNM: FLT-PET predicts survival in patients with brain tumorsClinical FDG-PET use grows as research move forwardMR and PET strategies identify optimal biopsy sampling sites for malignant gliomas